Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis
Advanced metastatic colorectal cancer (CRC) with deficient DNA mismatch repair (MMR-d), or immune-hot CRCs, show significantly improved clinical outcomes compared to MMR-proficient (MMR-p), or immune-cold CRCs. While the prior represents about 5% of all CRCs, the latter represent 95% and are charact...
Saved in:
| Main Authors: | , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Frontiers Media S.A.
2025-02-01
|
| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1491450/full |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823856585006383104 |
|---|---|
| author | Daciana C. Dumut Daciana C. Dumut Marian Hajduch Marian Hajduch Amanda M. Zacharias Qingling Duan Qingling Duan Ivo Frydrych Zuzana Rozankova Zuzana Rozankova Miroslav Popper Miroslav Popper Dusan Garic Radu Alexandru Paun Radu Alexandru Paun Amanda Centorame Amanda Centorame Juhi Shah Martin Mistrik Martin Mistrik Petr Dzubak Petr Dzubak Juan B. De Sanctis Juan B. De Sanctis Danuta Radzioch Danuta Radzioch Danuta Radzioch Danuta Radzioch |
| author_facet | Daciana C. Dumut Daciana C. Dumut Marian Hajduch Marian Hajduch Amanda M. Zacharias Qingling Duan Qingling Duan Ivo Frydrych Zuzana Rozankova Zuzana Rozankova Miroslav Popper Miroslav Popper Dusan Garic Radu Alexandru Paun Radu Alexandru Paun Amanda Centorame Amanda Centorame Juhi Shah Martin Mistrik Martin Mistrik Petr Dzubak Petr Dzubak Juan B. De Sanctis Juan B. De Sanctis Danuta Radzioch Danuta Radzioch Danuta Radzioch Danuta Radzioch |
| author_sort | Daciana C. Dumut |
| collection | DOAJ |
| description | Advanced metastatic colorectal cancer (CRC) with deficient DNA mismatch repair (MMR-d), or immune-hot CRCs, show significantly improved clinical outcomes compared to MMR-proficient (MMR-p), or immune-cold CRCs. While the prior represents about 5% of all CRCs, the latter represent 95% and are characterized by low immunogenicity. This study investigates bis-diethyldithiocarbamate (CuET), a novel anticancer compound, and its impact on the colorectal cancer tumor microenvironment (TME). CuET is shown to convert immunologically inactive tumors into hotbeds of antitumor immune responses, marked by increased lymphocyte infiltration, heightened cytotoxicity of natural killer (NK) and T cells, and enhanced non-self recognition by lymphocytes. The potent anticancer cytotoxicity and in vivo safety and efficacy of CuET are established. In summary, CuET transforms the colorectal cancer TME, bolstering NK and T cell cytotoxicity and refining tumor cell recognition through non-classical activation via the NKG2D/NKG2DL axis. This study unveils a novel mechanism of action for CuET: a potent immunomodulator capable of turning cold tumors hot. |
| format | Article |
| id | doaj-art-63374aafeb1d4b008a513ba94caf46c0 |
| institution | Kabale University |
| issn | 1664-3224 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj-art-63374aafeb1d4b008a513ba94caf46c02025-02-12T07:25:34ZengFrontiers Media S.A.Frontiers in Immunology1664-32242025-02-011610.3389/fimmu.2025.14914501491450Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axisDaciana C. Dumut0Daciana C. Dumut1Marian Hajduch2Marian Hajduch3Amanda M. Zacharias4Qingling Duan5Qingling Duan6Ivo Frydrych7Zuzana Rozankova8Zuzana Rozankova9Miroslav Popper10Miroslav Popper11Dusan Garic12Radu Alexandru Paun13Radu Alexandru Paun14Amanda Centorame15Amanda Centorame16Juhi Shah17Martin Mistrik18Martin Mistrik19Petr Dzubak20Petr Dzubak21Juan B. De Sanctis22Juan B. De Sanctis23Danuta Radzioch24Danuta Radzioch25Danuta Radzioch26Danuta Radzioch27Department of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC, CanadaThe Research Institute of the McGill University Health Centre, Infectious Diseases in Global Health Program, Montreal, QC, CanadaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, CzechiaCzech Advanced Technology and Research Institute, Palacky University Olomouc, Olomouc, CzechiaDepartment of Biomedical & Molecular Sciences, Faculty of Health Sciences, Queen’s University, Kingston, ON, CanadaDepartment of Biomedical & Molecular Sciences, Faculty of Health Sciences, Queen’s University, Kingston, ON, CanadaSchool of Computing, Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, ON, CanadaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, CzechiaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, CzechiaCzech Advanced Technology and Research Institute, Palacky University Olomouc, Olomouc, CzechiaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, CzechiaCzech Advanced Technology and Research Institute, Palacky University Olomouc, Olomouc, CzechiaDepartment of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, TN, United StatesThe Research Institute of the McGill University Health Centre, Infectious Diseases in Global Health Program, Montreal, QC, CanadaDepartment of Biomedical Engineering, McGill University, Montreal, QC, CanadaDepartment of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC, CanadaThe Research Institute of the McGill University Health Centre, Infectious Diseases in Global Health Program, Montreal, QC, CanadaThe Research Institute of the McGill University Health Centre, Infectious Diseases in Global Health Program, Montreal, QC, CanadaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, CzechiaCzech Advanced Technology and Research Institute, Palacky University Olomouc, Olomouc, CzechiaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, CzechiaCzech Advanced Technology and Research Institute, Palacky University Olomouc, Olomouc, CzechiaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, CzechiaCzech Advanced Technology and Research Institute, Palacky University Olomouc, Olomouc, CzechiaDepartment of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC, CanadaThe Research Institute of the McGill University Health Centre, Infectious Diseases in Global Health Program, Montreal, QC, CanadaInstitute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, CzechiaCzech Advanced Technology and Research Institute, Palacky University Olomouc, Olomouc, CzechiaAdvanced metastatic colorectal cancer (CRC) with deficient DNA mismatch repair (MMR-d), or immune-hot CRCs, show significantly improved clinical outcomes compared to MMR-proficient (MMR-p), or immune-cold CRCs. While the prior represents about 5% of all CRCs, the latter represent 95% and are characterized by low immunogenicity. This study investigates bis-diethyldithiocarbamate (CuET), a novel anticancer compound, and its impact on the colorectal cancer tumor microenvironment (TME). CuET is shown to convert immunologically inactive tumors into hotbeds of antitumor immune responses, marked by increased lymphocyte infiltration, heightened cytotoxicity of natural killer (NK) and T cells, and enhanced non-self recognition by lymphocytes. The potent anticancer cytotoxicity and in vivo safety and efficacy of CuET are established. In summary, CuET transforms the colorectal cancer TME, bolstering NK and T cell cytotoxicity and refining tumor cell recognition through non-classical activation via the NKG2D/NKG2DL axis. This study unveils a novel mechanism of action for CuET: a potent immunomodulator capable of turning cold tumors hot.https://www.frontiersin.org/articles/10.3389/fimmu.2025.1491450/fullcopper bis-diethyldithiocarbamatedisulfiramcolorectal cancerNK cellsNKG2D |
| spellingShingle | Daciana C. Dumut Daciana C. Dumut Marian Hajduch Marian Hajduch Amanda M. Zacharias Qingling Duan Qingling Duan Ivo Frydrych Zuzana Rozankova Zuzana Rozankova Miroslav Popper Miroslav Popper Dusan Garic Radu Alexandru Paun Radu Alexandru Paun Amanda Centorame Amanda Centorame Juhi Shah Martin Mistrik Martin Mistrik Petr Dzubak Petr Dzubak Juan B. De Sanctis Juan B. De Sanctis Danuta Radzioch Danuta Radzioch Danuta Radzioch Danuta Radzioch Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis Frontiers in Immunology copper bis-diethyldithiocarbamate disulfiram colorectal cancer NK cells NKG2D |
| title | Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis |
| title_full | Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis |
| title_fullStr | Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis |
| title_full_unstemmed | Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis |
| title_short | Diethyldithiocarbamate-copper complex ignites the tumor microenvironment through NKG2D-NKG2DL axis |
| title_sort | diethyldithiocarbamate copper complex ignites the tumor microenvironment through nkg2d nkg2dl axis |
| topic | copper bis-diethyldithiocarbamate disulfiram colorectal cancer NK cells NKG2D |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2025.1491450/full |
| work_keys_str_mv | AT dacianacdumut diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT dacianacdumut diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT marianhajduch diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT marianhajduch diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT amandamzacharias diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT qinglingduan diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT qinglingduan diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT ivofrydrych diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT zuzanarozankova diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT zuzanarozankova diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT miroslavpopper diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT miroslavpopper diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT dusangaric diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT radualexandrupaun diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT radualexandrupaun diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT amandacentorame diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT amandacentorame diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT juhishah diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT martinmistrik diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT martinmistrik diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT petrdzubak diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT petrdzubak diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT juanbdesanctis diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT juanbdesanctis diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT danutaradzioch diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT danutaradzioch diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT danutaradzioch diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis AT danutaradzioch diethyldithiocarbamatecoppercomplexignitesthetumormicroenvironmentthroughnkg2dnkg2dlaxis |